It is becoming increasingly clear that cancer is a complex genetic disease, not just because of the number of distinct histological types, but also because of genetic and phenotypic variation between individuals that can influence susceptibility to disease development, tumor progression or responses to therapy. Heterogeneity is seen both at the level of the combinations of somatic genetic events and gene expression changes in tumors, and in the patterns of inherited genetic variants (SNPs) in the normal host DNA. In addition, complex interactions exist between the genetics of the host and environmental exposures that contribute to tumor susceptibility. The Cancer Genetics Program is dedicated to the elucidation of the genetics of tumor susceptibility, tumorigenesis and progression, and to the utilization of this information clinically to improve cancer management. The program brings together 36 program members with expertise in the application of advanced genomic and genetic analysis tools to identify abnormalities that contribute to cancer genesis and progression, utilizing the outstanding clinical and patient resources at UCSF. The program also has close contact with the mouse models of cancer group at UCSF, and together we are building a comparative mouse-human approach to the genetics of susceptibility. A major new effort has been launched to develop a Systems Genetics approach to cancer, in close collaboration with the Lawrence Berkeley National Laboratory (LBNL). The Program Leaders have identified the following four central themes that we aim to develop in the next five years: (1) germline and environmental determinants of cancer susceptibility (John Witte);(2) cancer genome and epigenome analysis (Donna Albertson and Joseph Costello);(3) systems genetics of cancer (Joe Gray and Allan Balmain);and (4) statistical approaches to analysis of large scale cancer data sets (Neil Risch and Ajay Jain). The Program Members are fully integrated into the organ-sitespecific programs, and participate broadly in joint seminars and discussion groups with the human genetics program. In addition, the Program organizes a monthly cancer genetics discussion forum, with a view to encouraging cross-cutting research that encompasses both germline and somatic approaches to understanding the genetics of cancer. The Program has $12,940,579 Total peer reviewed support for the last budget year. The Program has 17% intra-programmatic and 43% inter-programmatic publications.